Seminars

Systems consolidation reorganizes hippocampal engram circuitry

n the neurosciences the need for some 'overarching' theory is sometimes expressed, but it is not always obvious what is meant by this. One can perhaps agree that in modern science observation and experimentation is normally complemented by 'theory', i.e. the development of theoretical concepts that help guiding and evaluating experiments and measurements. A deeper discussion of 'brain theory' will require the clarification of some further distictions, in particular: theory vs. model and brain research (and its theory) vs. neuroscience. Other questions are: Does a theory require mathematics? Or even differential equations? Today it is often taken for granted that the whole universe including everything in it, for example humans, animals, and plants, can be adequately treated by physics and therefore theoretical physics is the overarching theory. Even if this is the case, it has turned out that in some particular parts of physics (the historical example is thermodynamics) it may be useful to simplify the theory by introducing additional theoretical concepts that can in principle be 'reduced' to more complex descriptions on the 'microscopic' level of basic physical particals and forces. In this sense, brain theory may be regarded as part of theoretical neuroscience, which is inside biophysics and therefore inside physics, or theoretical physics. Still, in neuroscience and brain research, additional concepts are typically used to describe results and help guiding experimentation that are 'outside' physics, beginning with neurons and synapses, names of brain parts and areas, up to concepts like 'learning', 'motivation', 'attention'. Certainly, we do not yet have one theory that includes all these concepts. So 'brain theory' is still in a 'pre-newtonian' state. However, it may still be useful to understand in general the relations between a larger theory and its 'parts', or between microscopic and macroscopic theories, or between theories at different 'levels' of description. This is what I plan to do.

In 2023, the FlyWire Consortium released the neuronal wiring diagram of an adult fly brain. This contains as a corollary the first complete wiring diagram of a visual system, which has been used to identify all 200+ cell types that are intrinsic to the Drosophila optic lobe. About half of these cell types were previously unknown, and less than 20% have ever been recorded by a physiologist. I will argue that plausible functions for many cell types can be guessed by interpreting the wiring diagram. VVTNS Fifth Season Closing Lecture. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-06-25. Recording duration: 00:42:39.

We introduce a statistical physics framework for learning in neural architectures composed of single or interconnected asymmetric attractor networks. These systems can exhibit a manifold of global fixed points capable of implementing sophisticated input-output mappings, which we characterize analytically. Learning from extensive datasets is achieved through the stabilization of fixed points via a fully distributed and local learning process, implemented at the single-neuron level. This simple mechanism yields performance comparable to that of conventional feedforward deep neural networks trained using gradient-based methods. The effectiveness of the model stems from the dense and accessible manifolds of stable fixed points, which encode the internal representations of data. Unlike other approaches to deep learning without backpropagation, our method does not attempt to estimate gradients. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-06-18. Recording duration: 00:45:35.

Neocortical synaptic engrams for remote contextual memories

Sleep is an active state critical for processing emotional memories encoded during waking in both humans and animals. There is a remarkable overlap between the brain structures and circuits active during sleep, particularly rapid eye-movement (REM) sleep, and the those encoding emotions. Accordingly, disruptions in sleep quality or quantity, including REM sleep, are often associated with, and precede the onset of, nearly all affective psychiatric and mood disorders. In this context, a major biomedical challenge is to better understand the underlying mechanisms of the relationship between (REM) sleep and emotion encoding to improve treatments for mental health. This lecture will summarize our investigation of the cellular and circuit mechanisms underlying sleep architecture, sleep oscillations, and local brain dynamics across sleep-wake states using electrophysiological recordings combined with single-cell calcium imaging or optogenetics. The presentation will detail the discovery of a 'somato-dendritic decoupling'in prefrontal cortex pyramidal neurons underlying REM sleep-dependent stabilization of optimal emotional memory traces. This decoupling reflects a tonic inhibition at the somas of pyramidal cells, occurring simultaneously with a selective disinhibition of their dendritic arbors selectively during REM sleep. Recent findings on REM sleep-dependent subcortical inputs and neuromodulation of this decoupling will be discussed in the context of synaptic plasticity and the optimization of emotional responses in the maintenance of mental health.

In a first part of the talk, I will present Predictive Coding Light (PCL), a novel unsupervised learning architecture for spiking neural networks. In contrast to conventional predictive coding approaches, which only transmit prediction errors to higher processing stages, PCL learns inhibitory lateral and top-down connectivity to suppress the most predictable spikes and passes a compressed representation of the input to higher processing stages. We show that PCL reproduces a range of biological findings and exhibits a favorable tradeoff between energy consumption and downstream classification performance on challenging benchmarks. A second part of the talk will feature our lab’s efforts to explain how infants and toddlers might learn abstract object representations without supervision. I will present deep learning models that exploit the temporal and multimodal structure of their sensory inputs to learn representations of individual objects, object categories, or abstract super-categories such as „kitchen object“ in a fully unsupervised fashion. These models offer a parsimonious account of how abstract semantic knowledge may be rooted in children's embodied first-person experiences.

Understanding how brains learn requires bridging evidence across scales—from behaviour and neural circuits to cells, synapses, and molecules. In our work, we use computational modelling and data analysis to explore how the physical properties of neurons and neural circuits constrain learning. These include limits imposed by brain wiring, energy availability, molecular noise, and the 3D structure of dendritic spines. In this talk I will describe one such project testing if wiring motifs from fly brain connectomes can improve performance of reservoir computers, a type of recurrent neural network. The hope is that these insights into brain learning will lead to improved learning algorithms for artificial systems.

We developed a novel paradigm measuring implicit identity recognition using Fast Periodic Visual Stimulation (FPVS) with EEG among 16 students and 12 police officers with normal face processing abilities. Participants' neural responses to a 1-Hz tagged oddball identity embedded within a 6-Hz image stream revealed implicit recognition with high-quality mugshots but not CCTV-like images, suggesting optimal resolution requirements. Our findings extend previous research by demonstrating that even unfamiliar identities can elicit robust neural recognition signatures through brief, repeated passive exposure. This approach offers potential for objective validation of face processing abilities in forensic applications, including assessment of facial examiners, Super-Recognisers, and eyewitnesses, potentially overcoming limitations of traditional behavioral assessment methods.

Astrocytes release glutamate by regulated exocytosis in health and disease Vladimir Parpura, International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, P.R. China Parpura will present you with the evidence that astrocytes, a subtype of glial cells in the brain, can exocytotically release the neurotransmitter glutamate and how this release is regulated. Spatiotemporal characteristic of vesicular fusion that underlie glutamate release in astrocytes will be discussed. He will also present data on a translational project in which this release pathway can be targeted for the treatment of glioblastoma, the deadliest brain cancer.

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. By re-analyzing RNA-sequencing datasets from human FTD/ALS brains, we discovered dozens of novel cryptic splicing events in important neuronal genes. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies, but how those variants increase risk for disease is unknown. We discovered that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harboring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function. Recent analyses have revealed even further changes in TDP-43 target genes, including widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

Structure and function of the hippocampal CA3 module

Measurements from hippocampal place cells in small enclosures have led to a classical view of highly stereotyped neural tuning functions with smooth, unimodal tuning fields that uniformly tile the environment. However, recent experiments conducted in large spaces across multiple species have revealed a much more irregular neural code than suggested by the classical view. Indeed, place cells in large environments typically fire in multiple locations, and the multiple firing fields of individual cells, as well as those of the entire population, vary considerably in size and shape. We recently showed that a simple mathematical model, wherein firing fields are generated by thresholding realizations of a random Gaussian process, accounts for the statistical properties of place fields in precise quantitative detail. This model captures the observed statistics of field sizes and positions and generates new quantitative predictions on field shapes and topologies. Moreover, these statistics are universal across species, but sensitive to the size and dimensionality of the environment. We quantitatively verified these predictions using multiple recent datasets from bats and rodents in one, two, and three dimensions, across both small and large environments. Collectively, these findings imply that common mechanism underlie the diverse statistical features observed in different experiments and suggest that synaptic projections to CA1 are predominantly random. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-05-28. Recording duration: 00:42:45.

Recent advances in artificial intelligence have led to new forms of misinformation, including highly realistic “deepfake” synthetic media. We conduct three experiments to investigate how and why retail investors react to deepfake financial news. Results from the first two experiments provide evidence that investors use a “realism heuristic,” responding more intensely to audio and video deepfakes as their perceptual realism increases. In the third experiment, we introduce an intervention to prompt analytical thinking, varying whether participants make analytical judgments about credibility or intuitive investment judgments. When making intuitive investment judgments, investors are strongly influenced by both more and less realistic deepfakes. When making analytical credibility judgments, investors are able to discern the non-credibility of less realistic deepfakes but struggle with more realistic deepfakes. Thus, while analytical thinking can reduce the impact of less realistic deepfakes, highly realistic deepfakes are able to overcome this analytical scrutiny. Our results suggest that deepfake financial news poses novel threats to investors.

When we attend a demanding task, our performance is poor at low arousal (when drowsy) or high arousal (when anxious), but we achieve optimal performance at intermediate arousal. This celebrated Yerkes-Dodson inverted-U law relating performance and arousal is colloquially referred to as being "in the zone." In this talk, I will elucidate the behavioral and neural mechanisms linking arousal and performance under the Yerkes-Dodson law in a mouse model. During decision-making tasks, mice express an array of discrete strategies, whereby the optimal strategy occurs at intermediate arousal, measured by pupil, consistent with the inverted-U law. Population recordings from the auditory cortex (A1) further revealed that sound encoding is optimal at intermediate arousal. To explain the computational principle underlying this inverted-U law, we modeled the A1 circuit as a spiking network with excitatory/inhibitory clusters, based on the observed functional clusters in A1. Arousal induced a transition from a multi-attractor (low arousal) to a single attractor phase (high arousal), and performance is optimized at the transition point. The model also predicts stimulus- and arousal-induced modulations of neural variability, which we confirmed in the data. Our theory suggests that a single unifying dynamical principle, phase transitions in metastable dynamics, underlies both the inverted-U law of optimal performance and state-dependent modulations of neural variability.